Li Wen, M.D., Ph.D. Research Scientist Section of Endocrinology Department of Internal Medicine 333 Cedar Street P.O. Box 208020 New Haven, CT 06520-8020 USA Email: li.wen@yale.edu Telephone: (203) 785-7186

• M.D., Capital College of Medicine, Beijing, China, 1983
• Ph.D., Immunology, King's College, London, UK, 1992

Research

Our research interest lies mainly in autoimmunity. Type 1 diabetes is a polygenetic autoimmune disease and the major susceptibility gene is in the human leukocyte antigen (HLA) region. The common HLA seen in patients with type 1 diabetes is in the DR4-DQ8 haplotype. We have generated novel transgenic HLA/RIP-B7 mouse models that develop spontaneous diabetes. The only MHC class II molecules expressed (as transgene) in these mice are humna HLA-DQ8, -DR4, -DQ8DR4 or -DQ6. Our striking finding is that introduction of human HLA-DQ8 or DR4 causes RIP-B7 mice (on C57BL/6 genetic background), that are normally resistant to diabetes, to become diabetic spontaneously. The DQ8/RIP-B7 mice develop the highest incidence of spontaneous diabetes (~80%), whereas DR4/RIP-B7 and DQ8DR4/RIP-B7 mice develop a lower incidence of diabetes (~25%). However, when human diabetes susceptibility molecules (DQ8 or DR4) were replaced in these mice by non-susceptibility molecules, such as HLA-DQ6, diabetes was completely prevented. Our study clearly shows that it is human HLA molecules that make the difference in promoting or preventing the diabetes development. Our "humanized" spontaneous diabetes model provides us not only a novel means to study the immunopathological effect of human individual genes in diabetes development, this may also facilitate the development of new theraputic strategies for the treatment of the disease.